Abstract
Resistin has been linked to obesity, insulin resistance, atherosclerosis, and the development of cardiovascular disease. Nevertheless, the effects and the molecular mechanisms of resistin on endothelial permeability, a key event in the development of atherosclerosis, inflammation, and vascular disease, are largely unknown. In order to determine the effect of resistin on endothelial permeability, human coronary artery endothelial cells (HCAECs) were treated with clinically relevant concentrations of resistin and the endothelial permeability was measured using the Transwell system with a Texas-Red-labeled dextran tracer. The permeability of HCAEC monolayers treated with resistin (80 ng/mL) was 51% higher than the permeability of control monolayers (P<0.05). The mRNA levels of tight junction proteins zonula occludens-1 (ZO-1) and occludin in resistin-treated cells were 37% and 42% lower, respectively, than the corresponding levels in untreated cells. The protein levels of these molecules in resistin-treated cells were significantly reduced by 35% and 37%, respectively (P<0.05), as shown by flow cytometry and Western blot analysis. Superoxide dismutase (SOD) mimetic MnTBAP effectively blocked the resistin-mediated reduction of ZO-1 and occludin levels in HCAECs. In addition, superoxide anion production was increased from 21% (untreated cells) to 55% (cells treated with 40 ng/mL resistin), and 64% (resistin, 80 mg/mL) (P<0.05). The natural antioxidant Ginkgolide A effectively inhibited resistin-induced increase in permeability and the increase in superoxide anion production in HCAECs. Furthermore, resistin treatment significantly activated p38 MAPK, but not ERK1/2. Pretreatment of HCAECs with a p38 inhibitor effectively blocked resistin-induced permeability. These results provide new evidence that resistin may contribute to the vascular lesion formation via increasing endothelial permeability through the mechanism of oxidative stress and the activation of p38 MAPK.
Highlights
Resistin is an adipokine that was discovered in 2001 and named for its resistance to insulin action
Resistin Increases Permeability in human coronary artery endothelial cells (HCAECs) Monolayers In order to determine the effect of resistin on the endothelial permeability, HCAEC monolayers were incubated with different concentrations of resistin and the permeability to Texas-Redlabeled dextran tracer was analyzed using a Costar Transwell system
Resistin Activates p38 Mitogen-activated protein kinases (MAPKs) in HCAECs In order to understand the signaling pathway involved in resistin-induced permeability in HCAECs, we investigated the possible involvement of major MAPKs, including extracellular signal-regulated kinase (ERK1/2), p38, and the c-Jun N-terminal protein kinase (JNK)
Summary
Resistin is an adipokine that was discovered in 2001 and named for its resistance to insulin action. Resistin has been associated with inflammatory markers, coronary artery disease, ovarian epithelial carcinoma, and cardiovascular disease (CVD) in the metabolic syndrome [9,10,11,12,13]. Several cytokines and growth factors, like tumor necrosis factora (TNF-a), interleukin-1b, and platelet-derived growth factor, can disrupt these junctional molecules and increase endothelial permeability [21,22]. Mitogen-activated protein kinases (MAPKs) and other signal molecules are involved in the regulation of endothelial permeability [23,24,25,26]. We examined the effect and potential molecular pathways of resistin on endothelial permeability in human coronary artery endothelial cells (HCAECs). Monolayer endothelial permeability, the expression of specific endothelial junction molecules, oxidative stress, and MAPK signal transduction molecules are investigated
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